There is a trend for synthetics to replace natural compounds in Prescription
and Over the Counter (OTC) Pharmaceuticals. Today, ephedrine, salicylates,
vitamins, and xanthines are mostly synthetic and steroids are often
semisynthetic. While agreeing with Farnsworth and Bingel (1977) that 25% of
modern prescription drugs contain at least one phytochemical, I suspect that
only about 10% or our leading drugs (excluding the illicit drugs, cocaine,
crack, hashish, heroin, marijuana, and opium) now contain phytochemicals still
extracted directly from the higher plants.

I draw on four major sources to support this contention: (1) Products of
America's largest pharmaceutical firms listed in the Physicians Desk Reference
(PDR 1991), (2) Reanalysis of Farnsworth and Bingel (1977), (3) Canadian OTC
Drugs (CPA 1988), and (4) Sittig's Encyclopedia (1988).

If only about 10% of the 100 most important major drugs (Sittig 1988) and the
PDR-listed drugs (PDR 1991) of major drug companies contain major compounds
still derived from plants, we must clarify the 25% figure (Farnsworth
and Bingel 1977) that conservationists have quoted and misquoted for twenty
years. Emphasizing the constancy of this 25%, Farnsworth et al. (1985)
reported: "In the USA, for example, 25% of all prescriptions dispensed from
community pharmacies from 1959 to 1980 contained plant extracts or active
principles prepared from higher plants. This figure (25%) did not vary by more
than ±1.0% in any of the 22 years surveyed ... and in 1980 consumers in the
USA paid more than $8,000 million for prescriptions containing active
principles obtained from plants." However, about 15% of those 25% are now
produced synthetically or semisynthetically and thus, no longer derived
directly from natural sources. Farnsworth and Bingel's (1977) estimate remains
correct if phrased as: 25% of modern prescription drugs contain at least one
compound now or once derived or patterned after compounds derived
from higher plants.

American consumers want natural drugs, believing natural drugs are safer than
synthetics. The pharmaceutical firms seem to prefer synthetics or
semisynthetics, in part due to proprietary economic reasons. The health of the
drug company by necessity must concern the drug company before the health of
the consumer. As noted in a recent International Trade Commission Study,
"Between 1976 and 1990, the cost of developing a pharmaceutical product in the
US increased from $54 million to $231 million. Only one out of every
4,000-10,000 compounds discovered can be marketed commercially--after which a
company has less than ten years to partially recoup its R&D investment
before its patent expires and generic manufacturers enter the market or a
me-too drug is created by a competitor" (Chemical Marketing Reporter 1991).
Such investments may lead pharmaceutical firms to prefer a proprietary
synthetic or semisynthetic to a relatively less proprietary herbal or natural
product. American pharmaceutical firms often seek the semisynthetic and avoid
the natural compound, when, at least in some cases, the natural compound might
be best. The pharmaceutical firm must consider several attributes including,
safety, efficacy, reproducibility of results, patentability, and profitability.
With at least $7,000 in public relations directed to each physician in this
country by the pharmaceutical firms, the physicians may reflect the same
priorities as the pharmaceutical firms. Consumers, National Institute of
Health, Food and Drug Administration, and the government as a whole should seek
the safest, cheapest, most efficacious drugs. Often, these could prove to be
standardized herbs or relatively unpatentable natural products, placing the
drug companies and the consumers and government's interests in conflict. More
than 10% of Americans can't even afford modern medicine and/or insurance.
Farnsworth (1990) estimates that about 64% of the world's population or 3.2
billion people use plants as drugs (largely unable to afford modern medicine).
If their drugs are worth as much to them economically as modern medicine is to
Americans, these plants are worth trillions of dollars.

What can be done to determine which natural alternatives are relatively safe,
efficacious, and affordable to the majority of the world's citizenry? There
must be some economic incentive for drug firms to investigate natural
alternatives. Clearly, it would not make sense for a drug firm to invest $231
million proving that a widely grown ornamental could prevent migraine, when the
drug firms are already reaping millions of dollars in the sale of proprietary
migraine medications. If, on the other hand, drug companies by mandate,
compared new synthetic drugs not only with placebo, but with one of the best
herbal alternatives, e.g. feverfew for migraine, those drug companies could be
given some marketing exclusivity on natural alternatives that the companies
prove efficacious. As a society, we would feel safer in the knowledge that
home-grown herbs had been proven efficacious, at least under the experimental
conditions.

American consumers are calling for greater use of natural products (certainly
they prefer natural antioxidants, cosmetics, dyes, food colors, and pesticides,
if not medicines) while the pharmaceutical firms have moved towards the
synthetic. It is hard to document the disdain for the natural compound among
the druggists. Farnsworth notes, however (1990):

"Of all the pharmaceutical companies I know in the US that are interested in
research on plant materials--and that's probably only four--none is interested
in discovering active chemical structures which will be patented and marketed
as drugs per se. They are looking for lead structures from which they would
prepare analogues."

The only pharmaceutical firms that I know in the United States that are
interested in natural products are Merck Sharp & Dohme (West Point,
Pennsylvania), Eastman Pharmaceuticals (Rochester, New York), SmithKline
Beecham (Pittsburg, Pennsylvania), and Glaxo (Research Triangle Park, North
Carolina). There are several small start-up companies, getting into this area
either from a mass screening viewpoint or from looking to ethnobotany e.g.
Shaman Pharmaceuticals (see King 1991), to provide leads. This is a new trend:
five years ago, there wasn't a single pharmaceutical company in the United
States that had any interest in developing drugs from higher plants."
(Farnsworth 1990).

Green consumerism has not yet reached the pharmaceutical industry. One might
define a "green" pharmaceutical as one containing as its major ingredient a
compound still commercially extracted from a higher plant. Estimated
percentages of "green" products produced by some major pharmaceutical firms are
tabulated in Table 1. Their drugs, as listed in PDR (1991), were evaluated to
see what percentage still contained natural products as one of the major
ingredients. The average for these firms is less than 10% "green." If all the
once-natural compounds, or compounds patterned after once-natural, and
excipients, such as acacia, candellila, carnauba, guar, tragacanth, are
included, then more than 50% of their drugs contain some naturally occurring
phytochemical. Thus, a sensu stricto interpretation (only still-natural
phytochemicals as major ingredients), finds fewer that 10% natural or "green"
pharmaceuticals. A sensu lato interpretation (containing a now-natural or
once-natural phytochemical as a major or minor ingredient), finds more
than half of modern pharmaceuticals are at least partially "green."

Table 2, modified from Farnsworth and Bingel (1977) lists the major
plant-derived phytochemicals in United States prescriptions two decades ago.
Steroids are clearly the largest items in Table 2. From mare's urine as a
source of steroids, we moved to temperate Dioscorea villosa, and then to
tropical "barbasco" (Dioscorea spp.). After too many price hikes in the
barbasco, the steroid industry largely went to semisynthetic modification of
the phytosterols from temperate soybeans. In general, most modern steroids are
now semisynthetic. Codeine, atropine, hyoscyamine, digoxin, digitoxin,
pilocarpine, and quinidine are still derived from plants. Reserpine,
pseudoephedrine, and ephedrine, count for 3% of those prescriptions cited by
Farnsworth and Bingel (1977), and are sometimes produced synthetically,
sometimes natural. Two-thirds of American ephedrine is synthetic, one-third
from German, one-third from American factories, the other third being natural
ephedrine from China. The relative share of the synthetic will probably
increase in the future. Assume that half of our ephedrine, pseudoephedrine,
and reserpine are synthetic and that all the steroids are now semisynthetic,
subtract and find that, accepting these assumptions and no change in
percentages, only 6.4% of our drugs have these natural ingredients, synthetic
or semisynthetic compounds having replaced the natural compounds.

In his first Table, Sittig (1988) lists the top 100 generic pharmaceuticals in
the United States in 1976. The top four items had sales over $100 million; the
cutoff after 100 was at the 10 million sales level. Total United States sales
of the top 100 was about $3 billion. Among the top 25 of Sittig, only one
(4%), is clearly derived largely from higher plants, digoxin from temperate
Digitalis as number 4. Theophylline once derived from subtropical
Camellia (and possibly tropical Theobroma), at number 21, is
still used but is almost if not exclusively synthesized. Methyldopa is
synthesized, but could possibly be based on the legumes like Mucuna and
Vicia which contain levodopa. Likewise, the hormones norethindrone,
ethinyl estradiol, and conjugated estrogens appear to be wholly synthesized or
semisynthetic but they could probably be derived from starting estrogenic
compounds in palm and pine pollens or pomegranates. Tartaric acid and
potassium chloride, e.g., also occur in higher plants but can be viewed as
phytochemicals.

Farther down Sittig's top 100, there are even fewer clearly "green" drugs.
There are several estrogenic or androgenic hormones, presumably largely
semisynthetic. There are several antibiotics derived from lower plants. Some
have salicylic or tartaric acids or maleic-acids, coumarin, ethanol,
furfurylamines, triethylamines, guanidine, benzaldehyde, proline, piperidine,
heptaldehydes, and some contain semisynthetic opiates. Natural products, if
they are used, are often only minor elements in a bigger formula. Stretching
to accept guaifenesin (largely guaiacol which could come from a tropical tree),
warfarin sodium (based largely on 4-hydroxy-coumarin, which could come from a
tropical tree), and "nicotine polacrillex" (presumably based on natural
nicotine which could be obtained from tropical trees (Duboisia) or weeds
(Nicotiana), only about 5% of the top hundred are based primarily on
higher plant phytochemicals. Ten percent are antibiotics derived from lower
plants, mostly bacteria by biotechnology. Only by counting all the "iffy" odds
and ends can one stretch the percentage to 25% containing at least one compound
that could conceivably be derived from a higher plant.

A fourth line of evidence (CPA 1988) confirms Farnsworth's 25% figure sensu
lato. As in the United States, Canadians share a desire to take more
responsibility for their own health care. An aging population and the
resulting strain on health care services will force consumers to take an even
greater role in years to come (CPA 1988).

The product monographs appendix of the CPA Book lists hundreds of apparently
approved medicines from A&C with Codeine to Zinkosalb, both of which
contain salicylic compounds which the American Indians once derived from
poplars, willows, and even wintergreens. Such compounds count in the
Farnsworth 25%, even though they are now synthetic.

A&C with Codeine illustrates the problems one encounters in trying to make
a survey of this type. It contains three major ingredients, the now-synthetic
acetylsalicylic acid, the sometimes synthesized caffeine, and the still natural
codeine. Thus, it clearly contains one natural ingredient, probably the most
expensive ingredient, codeine, still derived from the opium poppy. The
caffeine may be synthesized or may be a by-product of decaffeinated coffee.
The acetylsalicylic-acid could fall into the category called semisynthetic, if
derived by acetylation of natural salicylic acid, but today it is mostly a pure
synthetic, involving the utilization of no higher plant phytochemicals.

A and D Ointment is equally problematic. Vitamins A & D, as all vitamins,
could come from natural products. But most are not derived from higher plants
and all are synthesized (Harold Newmark pers. commun.). A and D Ointment would
be scored "non-green," the lanolin of course derived from animals. Vitamins
should be scored non-phytochemical ("non-green") unless the monograph specifies
that the vitamin is plant derived. Absorbine contains methyl-salicylate and
menthol, both natural products, now largely synthesized. Excipients like the
glycine and lactose in Acetest are, of course, not scored as major ingredients.
Similarly homatropine, while related to atropine, is treated here as a
synthetic. How should one score ACI-JEL vaginal buffer which contains some
herbal excipients like tragacanth and acacia, and compounds that do occur in
plants like acetic and ricinoleic acids which are cheaper as synthetics?
Resorcinol is scored synthetic though it too can be derived from umbelliferone.
Pseudoephedrine and ephedrine are sometimes synthesized. Although lidocaine is
said to have been patterned after gramine, it is not a phytochemical. Aloe in
After Burn certainly makes it score "green." Similarly the witch hazel, not
the salicylic acid in Aknoderm, makes it score "green." Listerine Antiseptic
contains 21.9% alcohol, 0.09% eucalyptol (cineole), 0.06% thymol, and 0.04%
menthol (all derivable from plants but probably synthetic).

This discussion illustrates the subjective nature of assigning economic values
to a very complicated and widely divergent phytomedicinal industry. A generous
scoring, allowing all vitamins and amino-acids, acetic acid, lactose, as major
or minor ingredients or excipients would give at least 50% "green." Thus, the
final percentage of plants or plant-derived extracts in modern pharmaceuticals
will ultimately depend upon your definition of phytomedicinal. Should such
natural compounds as alcohol, vinegar, citric acid, resorcinol, be included,
then well over 50%, perhaps 75% of medicines contain plant-derived
phytochemicals. Only by counting all of the following major naturals could one
score the Canadian OTC's as 25% "green" (CPA 1988): allantoin, benzoin, bran,
caffeine, camphor, caprylic-acid, charcoal, cineole, citric-acid, codeine,
cresol, ephedrine, guaiacol, lecithin , menthol, methylcellulose,
methylmorphine, pectin, phenol, pseudephedrine, salicylates, sorbitol,
tartaric-acid, turpentine, and undecylinic-acid.

Some argue that we would be better with more natural product medicines and
fewer synthetics. If reverting to natural medicines, which also prove safe and
efficacious, could also help save the rain forest, there's one more reason to
consider natural drugs. The government should consider requiring
pharmaceutical firms not only to prove their new drugs safe and efficacious,
but compare them not only to placebo, but also to one or more of the better
herbal alternatives. If energy costs remain as they are or become less
expensive, we should expect even more synthetics to replace naturals, in both
Prescription and OTC drugs. If energy costs get more expensive, or if "green"
consumers get louder, we may reverse the trend from natural to synthetic in
this country.

With American drug firms trending away from the natural product, the Japanese
are increasing their share of the world's natural product patents. Surveys
(Duke 1990) over the last four years have shown the Japanese percentage of the
world's natural product patents surge from 40 to 60%. In 1990, at least among
those natural-product patents reported in Phytotherapy Research, Japan obtained
more than five times more than did the United States (Table 3). As American
consumer demand for the natural increases, the pharmaceutical
dissatisfaction for the natural ironically also increases.